Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis

Abstract

Alterations in macroautophagy (hereafter referred to as “autophagy”) are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lipids to the lysosome via autophagy. The study summarized here describes novel methods for the interrogation of individual stages of the autophagic pathway, and suggests mechanisms by which lipid storage may result in broader lysosomal dysfunction.

Keywords: :

• Niemann-Pick
• autophagy
• lysosome
• lipid storage
• cholesterol
• cathepsin
• neurodegeneration

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Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by grants from the National Institutes of Health (grant number F31 NS065662 to M.J.E. and R01 NS063967 to A.P.L.).